Autoantibodies to the insulin receptor occur in patients with insulin resistance as well as patients with hypoglycemia. Both in vitro and in vivo studies on the effects of anti-receptor antibodies to mimic or antagonize insulin action have been studied. While all of these anti-receptor antibodies can mimic insulin action, some of the antisera fail to stimulate the receptor-associated kinase activity. Anti-receptor antibodies can also mimic the effect of insulin to down-regulate receptors by accelerating receptor degradation. This effect of anti-receptor antibodies may play an important role in the desensitization of the target cell to the effects of insulin and to the insulinomimetic effects of anti-receptor antibody. Anti-insulin antibodies have been used as a probe for the interaction between insulin and its receptor. Polyclonal anti-insulin antibodies can immunoprecipitate the cross-linked I125-insulin-receptor complex. Sixteen monoclonal antibodies failed to immunoprecipitate receptor-bound I125-insulin. One monoclonal antibody immunoprecipitated the cross-linked I125-insulin-receptor complex, albeit poorly. These data suggest that the majority of the epitopes on the insulin molecule become sterically unavailable for antibody binding.